Our long-term objectives are to understand how the central nervous system controls arterial pressure in both the normotensive and hypertensive state. Our focus is on the circumventricular organs (CVOs) of the brain. Because the blood-brain barrier is weak or absent in the CVOs, the circulating hypertensinogenic peptide angiotensin II is known to gain access to neurons in these structures and activate them electrophysiologically. One CVO, the area postrema (AP), is believed to have a role in angiotensin- mediated pressure increases in dog and rabbit, but there is little evidence to implicate the AP in hypertension in these species. In the rat, past investigations have revealed little or no role for the AP in cardiovascular regulation. Now, hovever, we have found that in the rat: (a) AP electrical stimulation increases arterial pressure and regional vascular resistance, and (b) AP ablation (APX) prevents several forms of experimental hypertension. Prevention of hypertension appears to occur without impairment of the baroreflex function of the nearby nucleus tractus solitarius. We propose to examine mechanisms whereby the AP may be involved in arterial pressure regulation. We have established that APX prevents hypertension. (1) In hypertension, total peripheral resistance is elevated; we will examine whether APX prevents hypertension via reductions in total peripheral resistance or cardiac output. (2) Expansion of body fluid volumes can lead to hypertension; we will examine whether APX prevents hypertension via reductions in body fluid volumes and/or enhanced excretion of urine or sodium. (3) Sympathetic nervous system overactivity has been documented in hypertensive models. Using recording of nerve traffic in the renal nerves, we will examine the hypothesis that APX blocks overactivity of the sympathetic nervous system in hypertension. (4) Finally, we will attempt to determine what neural elements in the AP region are critical for hypertension to occur. By applying directly to the AP a neurotoxin which is believed to spare fibers, we will kill AP neurons without damaging fibers. Whether this is sufficient to prevent hypertension will be assessed, along with the extent to which nearby neurons are damaged and whether fibers in the region are damaged.